Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension
Thomas Bertero, … , Joshua Fessel, Stephen Y. Chan
Thomas Bertero, … , Joshua Fessel, Stephen Y. Chan
Published August 22, 2016
Citation Information: J Clin Invest. 2016;126(9):3313-3335. https://doi.org/10.1172/JCI86387.
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Research Article Pulmonology Vascular biology

Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension

Abstract

Dysregulation of vascular stiffness and cellular metabolism occurs early in pulmonary hypertension (PH). However, the mechanisms by which biophysical properties of the vascular extracellular matrix (ECM) relate to metabolic processes important in PH remain undefined. In this work, we examined cultured pulmonary vascular cells and various types of PH-diseased lung tissue and determined that ECM stiffening resulted in mechanoactivation of the transcriptional coactivators YAP and TAZ (WWTR1). YAP/TAZ activation modulated metabolic enzymes, including glutaminase (GLS1), to coordinate glutaminolysis and glycolysis. Glutaminolysis, an anaplerotic pathway, replenished aspartate for anabolic biosynthesis, which was critical for sustaining proliferation and migration within stiff ECM. In vitro, GLS1 inhibition blocked aspartate production and reprogrammed cellular proliferation pathways, while application of aspartate restored proliferation. In the monocrotaline rat model of PH, pharmacologic modulation of pulmonary vascular stiffness and YAP-dependent mechanotransduction altered glutaminolysis, pulmonary vascular proliferation, and manifestations of PH. Additionally, pharmacologic targeting of GLS1 in this model ameliorated disease progression. Notably, evaluation of simian immunodeficiency virus–infected nonhuman primates and HIV-infected subjects revealed a correlation between YAP/TAZ–GLS activation and PH. These results indicate that ECM stiffening sustains vascular cell growth and migration through YAP/TAZ-dependent glutaminolysis and anaplerosis, and thereby link mechanical stimuli to dysregulated vascular metabolism. Furthermore, this study identifies potential metabolic drug targets for therapeutic development in PH.

Authors

Thomas Bertero, William M. Oldham, Katherine A. Cottrill, Sabrina Pisano, Rebecca R. Vanderpool, Qiujun Yu, Jingsi Zhao, Yiyin Tai, Ying Tang, Ying-Yi Zhang, Sofiya Rehman, Masataka Sugahara, Zhi Qi, John Gorcsan III, Sara O. Vargas, Rajan Saggar, Rajeev Saggar, W. Dean Wallace, David J. Ross, Kathleen J. Haley, Aaron B. Waxman, Victoria N. Parikh, Teresa De Marco, Priscilla Y. Hsue, Alison Morris, Marc A. Simon, Karen A. Norris, Cedric Gaggioli, Joseph Loscalzo, Joshua Fessel, Stephen Y. Chan

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Figure 9

Periarteriolar fibrillar collagen deposition correlates with increased GLS1, glutaminolysis, and aspartate production in primate examples of SIV-induced PAH.

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Periarteriolar fibrillar collagen deposition correlates with increased G...
(A–D) Rhesus macaques were infected with SIV and evaluated over the course of 6 and 10–12 months postinfection (mpi) as compared with before infection (BI). (A) In 13 of the 22 macaques infected by SIV, PAH was evident as assessed by RVSP and histologic remodeling (see Supplemental Figure 11A). (B) Picrosirius red stain revealed increased periarteriolar fibrillar collagen deposition in SIV-PAH. (C and D) Coimmunofluorescence microscopy revealed an increase of YAP1/GLS1 (C) and YAP1/PCNA (D) double-positive cells in diseased pulmonary arterioles. In all panels, mean expression in control groups was assigned a fold change of 1, to which relevant samples were compared. P values were derived from 1-way ANOVA and post-hoc Tukey’s tests in A, while 2-tailed Student’s t test was used for other comparisons (#P < 0.001). Scale bars: 50 μm. See also Supplemental Figure 11.